Veterinary compositions for the treatment of parasitic diseases

ABSTRACT

Micellar non-aqueous or aqueous compositions for the therapeutic treatment of animal diseases caused by parasitic worms or nematodes, comprising rafoxanide and specific combinations of solvents which act as stabilising and absorption-promoting agents. The solvents are selected from non-ionic surface-active agents such as Tween®-80 and from N-methylpyrrolidone, 2-pyrrolidone or dimetylsulfoxide. The compositions are easy to prepare, stable upon storage and can be administered orally, by injection or topically. With these formulations, an improvement of the efficacy of rafoxanide in the treatment of the diseases is observed.

RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S.patent application Ser. No. 10,220,393, filed Aug. 29, 2002, whichclaims priority to PCT/EP01/02037, filed Feb. 22, 2001, which claimspriority to EP 00104126.9, filed Feb. 29, 2000. the entirety of which isincorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention concerns compositions comprisingrafoxanide, the compositions being intended to be used in the veterinaryfield, and preferably for the treatment of parasitic diseases in farmand domestic animals, like the liver fluke or bot fly infestations.

BACKGROUND OF THE INVENTION

[0003] Rafoxanide is the generic name of3′-chloro-4′-(4-chlorophenoxy)-3,5-di-iodosalicylanilide. Rafoxanide issold, for example, by the company Pfizer Animal Health Inc., Zimbabwe,under the trade name Ranox®, or by the company Ventron, India.

[0004] It is known that rafoxanide is useful as an anthelmintic andfasciolicide agent and is active for the treatment of parasitic diseasesaffecting animals and caused by parasitic worms or nematodesinfestations.

[0005] It is also known that rafoxanide is extremely water insoluble(see for example Nessel, GB patent 1 472 385), its solubility in waterat 25° C. being approximately 0.005% weight/volume.

[0006] Attempts to improve the solubilisation of rafoxanide by addingsurfade-active agents in the composition have been made. The resultshave shown that in a 1% surface-active agent composition, the solubilityof rafoxanide is 0.14%.

[0007] This has the drawback that, when given orally, the absorption ofrafoxanide by the body is low. As a consequence, its plasmaconcentration in the body is also low, and the majority of the activesubstance is unabsorbed and excreted in the faeces. For example, theabsorption may be as low as 10% in non-gastric species, and only up to50% or less in ruminants where the rumen aids in the absorption process.

[0008] As far as the anthelmintic activity is directly related to theplasma concentration of rafoxanide, to achieve a sufficient plasmaconcentration, a high dose of rafoxanide must be given to the subject tobe treated, which is clearly economically disadvantageous.

[0009] Another solution would be to deliver the drug via injection, buthere again, rafoxanide has been shown to be irritating and it istherefore not desirable to inject it as such.

[0010] In addition, rafoxanide is known to persist in the bloodstream ofanimals and to bind strongly to protein in the blood. This can lead totoxicity, which is clearly undesirable in the case of animals which areslaughtered for human consumption.

[0011] Several studies have been conducted to improve the absorption ofrafoxanide by the body or its solubility in a composition which would beacceptable for administration.

[0012] Nessel (GB Patent 1 472 385) describes an aqueous compositionwhich contains rafoxanide, polyvinylpyrrolidone and a caustic agent likesodium hydroxide or the sodium salt of cholic acid, deoxycholic acid,stearic acid or isostearic acid. According to the author, the presenceof polyvinylpyrrolidone and of the caustic agent in the compositionenhances the solubility of the active agent to such an extent that anaqueous composition containing up to 7.5% of rafoxanide can be prepared.

[0013] However, polyvinylpyrrolidone is an expensive material and, asmentioned in Nessel, the molecular weight of the polyvinylpyrrolidonemolecules varies widely within the range of about 10,000 to about360,000. This causes a drawback in the use of polyvinylpyrrolidone sinceonly biologically pure grades of polyvinylpyrrolidone exempts ofpyrogens and other toxic materials and with a molecular weight of 3,000to 50,000 should be used.

[0014] In a similar manner, Lo et al. (U.S. Pat. No. 4,128,632)describes an aqueous composition which contains a complex of rafoxanideand polyvinylpyrrolidone. The process for the preparation of thecomposition differs from the process of Nessel by the use of a specificsolvent like acetone or glycerol formal, which can optionally be removedby evaporation. According to Lo et al., the advantage over Nessel isthat the process is faster and less expensive since it does not requirethe expensive step of spray-drying of therafoxanide/polyvinylpyrrolidone complex formed in the solvent before itsdissolution in water.

[0015] However, in addition to the drawbacks mentioned above for thecompositions of Nessel and which are due to the use ofpolyvinylpyrrolidone, the compositions of Lo et al. may also containtraces of acetone, which is a toxic chemical compound not desired inveterinary or pharmaceutical compositions.

[0016] It should also be noted that the processes of Nessel or Lo et al.both contain a step of heating the composition at a temperature higherthan +40° C. which, at an industrial level, is an expensive andinconvenient step.

[0017] In another reference, Burke (WO 95/16447) describes ananthelmintic composition for oral administration containing 4.5%rafoxanide and 3% of another insoluble nematocidal agent belonging tothe benzimidazole derivatives, fenbendazole. The compositions aremicronised compositions, i.e. in the form of a suspension of particles,and contain also several additional components such as xanthan gum,polyvinylpyrrolidone and a dispersing agent. The author reports that thecomposition shows an improved anthelmintic effect without undesirabletoxic side effects. The improved effect is connected with an increasedplasma concentration of fenbendazole, originated by the combinedadministration of both agents. However, no improvement of the absorptionof rafoxanide is reported.

[0018] From the above examples, it can be concluded that there is stilla need for a composition for the treatment of parasitic diseases inanimals which is based on the active substance rafoxanide, which can beprepared in an easy way, which is sufficiently concentrated to permitsatisfactory dosage forms and which, when administered parenterally,topically or orally, shows good absorption characteristics by the body.

[0019] Surprisingly, the inventor of the present invention has foundthat the efficacy of rafoxanide in the treatment of parasitic diseasesin animals is improved when it is dissolved in a specific combination ofsolvents which is able to keep the active molecule in a micellar stablestate in the composition even at high concentrations. Thus, theresulting composition is a non-aqueous micellar composition.

[0020] A stable composition in the meaning of the present invention is acomposition wherein the compounds are present in a soluble form, i.e.there is for example no precipitate, the composition also remainingstable during storage.

[0021] The inventor of the present invention has also found that, ifnecessary, water can be added to the composition, to obtain an aqueousmicellar composition.

[0022] The inventor of the present invention has also found that saidcompositions are particularly effective in the treatment of parasiticworms or nematodes infestations in animals, like for example the liverfluke in cattle, buffaloes, sheep and goats, the blood sucking nematodesinfestations, and the larval stages of the nasal bot fly infestation insheep and goats.

[0023] Thus, the main object of the present invention is to provide newanthelmintic and fasciolicide compositions.

[0024] Another object of the present invention is to provide thesecompositions as compositions which are stable upon storage.

[0025] Another object of the present invention is to provide thesecompositions as compositions which can be administered orally, topicallyor parenterally (e.g. by injection).

[0026] One of the advantages of the present invention is therefore thatthe composition can be prepared in an easy manner, i.e. by simply mixingthe components together, and without the addition of expensive or toxicsubstances.

[0027] Another advantage of the present invention is that thecompositions have good absorption characteristics when compared to theabove mentioned known compositions of the prior art.

[0028] Further problems which can be solved by this invention withrespect to known prior art compositions will become apparent to thereader of the following description.

SUMMARY OF THE INVENTION

[0029] The present invention provides a solution to the aforementionedproblems.

[0030] The aforementioned object is achieved by a micellar compositionhaving the features defined in claim 1 and comprising as an essentialactive ingredient rafoxanide and a combination of solvents which act asa stabilizing and absorption-promoting agent, the combination beingselected from a group consisting of specific combinations of a non-ionicsurface active agent such as Tween® 80 with N-methylpyrrolidone (NMP),2-pyrrolidone, dimethylsulfoxide (DMSO), or specific combinationsthereof.

[0031] The aforementioned object is also achieved by the use of themicellar composition for the treatment of diseases, and most preferablydiseases due to parasitic worms or nematodes infestations in animalslike sheep, goats, buffalos or cattle.

[0032] Preferred embodiments of the invention, including the use ofpreferred concentrations, the addition of optional ingredients in thecomposition like for example glycerol formal, water, excipients,preservatives, vitamins, further stabilizing agents, carriers,antioxidants, photostabilizers, colorants, further absorption-promotingsubstances, or the use of the composition for the treatment of specificdiseases in animal are defined in the dependent claims.

[0033] A combination of anthelmintic antibiotics selected from the groupconsisting of avermectins or their derivatives, such as avermectin andivermectin, with the micellar composition comprising rafoxanide asdefined in claim 1, and the use of this combination for the treatment ofspecific diseases in animal, are also defined in the dependent claims.

[0034] Unless otherwise specified, the percentages of ingredients usedin the compositions are defined as weight per volume. The preferredconcentrations or ranges of concentrations mentioned hereafter areconcentrations which are more suitable to achieve the object of thepresent invention.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0035] The micellar composition according to the present inventioncomprises as an essential active ingredient rafoxanide and a combinationof solvents which act as a stabilising and absorption-promoting agent.

[0036] The amount of rafoxanide in the composition is preferably between2.5 and 25% weight/volume. Most preferably, the composition contains12.5% weight/volume of rafoxanide.

[0037] The combination of solvents which act as a stabilising andabsorption-promoting agent always comprise a non-ionic surface activeagent such as Tween® 80 (commercial name of polyoxyethylene sorbitanmonooleate) or Cremophor® (commercial name of polyoxyethylated castoroil), which is necessary for the formation of the micelles, and at leasta further solvent selected from N-methylpyrrolidone (NMP), 2-pyrrolidoneand dimethylsulfoxide (DMSO).

[0038] Preferably, the combination of solvents is a combination ofTween® 80 with NMP, or Tween® 80 with 2-pyrrolidone, or Tween® 80 withNMP and 2-pyrrolidone, or Tween® 80 with DMSO and NMP and/or2-pyrrolidone. These combinations may contain additionally glycerolformal, which acts as filler or cosolvent.

[0039] It should be noted that when DMSO and/or glycerol formal are theonly solvents added in a composition containing rafoxanide and Tween®80, a precipitate will form when the composition is kept at a lowtemperature. Therefore, it is recommended to always combine DMSO and/orglycerol formal with either NMP or 2-pyrrolidone.

[0040] The amount of Tween® 80 in the composition is preferably between5% and 50% weight/volume.

[0041] The compositions may also comprise optionally other agents likeexcipients, preservatives, vitamins, further stabilising agents,carriers, antioxidants, photostabilisers, colorants, furtherabsorption-promoting substances, thickeners or any other agent oradditive commonly used in veterinary or medical compositions which isfor example useful for the stability of the composition or permits toimprove the formulation for a specific way of administration withoutaltering the anthelmintic or fasciolicide activity.

[0042] When necessary, the composition may be diluted with water, inorder to obtain an aqueous micellar composition. Acetic acid should thenbe added in the composition to improve the stability and solubility ofthe components in the composition.

[0043] The composition may also comprise in addition an anthelminticantibiotic selected from the group consisting of avermectins or theirderivatives, such as for example avermectin or ivermectin.

[0044] Avermectins were isolated as compounds possessing anthelminticactivity from the culture broth of an actinomycete strain. Chemically,avermectins are oleandrose disaccharide derivatives of 16-memberedpentacyclic lactones. The avermectin complex is a family of four closelyrelated major components, A1a, A2a, B1a and B2a, and four minorcomponents, A1b, A2b, B1b and B2b, which are lower homologues of themajor components. Ivermectin, an hydrogenated product of the B1component (22,23-dihydroavermectin B1), is used as an importantanthelmintic in veterinary fields and for the control of onchocerciasisin human.

[0045] When combining avermectin or ivermectin with rafoxanide in acomposition in accordance with the present invention, the composition isespecially indicated for the treatment of diseases caused by internaland external parasites affecting cattle, buffaloes, sheep and goats.Examples of internal parasites aimed at are adult and immature roundworms, young (6 to 10 weeks old) and adult liver flukes, and tissueinvading fly maggots such as larvae of cattle warble fly and sheepnostril fly. Examples of external parasites aimed at are parasitescausing mange, ticks and lice.

[0046] The amount of avermectin or ivermectin in the composition ispreferably between 0% and 15% weight/volume.

[0047] The preferred combination is a combination of rafoxanide withivermectin. The best ratio between rafoxanide and ivermectin in thecomposition, or in other words the ratio that provides the best effect,can be easily determined via a routine experiment. In one embodiment,the composition preferably comprises 12% of rafoxanide and 0.8% ofivermectin.

[0048] Generally, the compositions are intended to be administeredorally, topically or by injection and will be prepared in a suitableform. However, it should be noted that the form in which thecompositions are administered depends upon the particular infection tobe treated and may be adapted in order, for example, to deliver theagent closer to the site of infection. Thus, in the case of infectionsof a topical nature, a formulation for topical application may beprepared and topical application may be used.

[0049] The compositions are effective for the treatment of diseases inanimals, in particular the treatment of infestations by parasitic wormsor nematodes in animals,

[0050] The parasitic worms or nematodes include, for example, worms ornematodes of the following types: Fasciola hepatica, Fasciola gigantica,Haemonchus placei, Bunostomum phlebotomum and Oesophagostomum radium.

[0051] In the case of a combination with avermectin or ivermectin, thecompositions are, as already mentioned above, more specificallyeffective for the treatment of diseases caused by internal and externalparasites affecting cattle, buffaloes, sheep and goats.

[0052] The posology and way of administration depend on the subject tobe treated and the stage and severity of the infestation.

[0053] For example, for systemic treatment of cattle infested by liverfluke, the composition is administered by subcutaneous injection andrafoxanide is given at a single dose of 3 mg/kg body weight.

[0054] In the case of a composition comprising a combination of 12%rafoxanide with 0.8% ivermectin, the composition may, for example, alsobe administered by subcutaneous injection such that rafoxanide is givenat a dose of 3 mg/kg body weight, and ivermectin is then given at a doseof 0.2 mg/kg body weight.

[0055] The invention will now be described in more detail with referenceto the following examples.

EXAMPLES

[0056] The amounts of ingredients are given in % of weight/volume. Thevolume is adjusted by addition of deionized water. The abbreviationq.s.p. means “quantity sufficient per”.

Example 1

[0057] A composition comprising: Rafoxanide 2.5% NMP   4% Tween ® 80 10% 2-pyrrolidone q.s.p. 100 ml

Example 2

[0058] A composition comprising: Rafoxanide 2.5% Tween ® 80   8% NMPq.s.p. 100 ml

Example 3

[0059] A composition comprising: Rafoxanide 2.5% 2-pyrrolidone  30%Tween ® 80  10% DMSO  20% NMP q.s.p. 100 ml

Example 4

[0060] A composition comprising: Rafoxanide 2.5% 2-pyrrolidone  20%Tween ® 80   8% NMP  20% Glycerol formal q.s.p. 100 ml

Example 5

[0061] A composition comprising: Rafoxanide 12.5% NMP   28% Tween ® 80  20% Glycerol formal q.s.p. 100 ml

Example 6

[0062] A composition comprising: Rafoxanide 15% Tween ®80 40% NMP q.s.p.100 ml

Example 7

[0063] A composition comprising: Rafoxanide 6.25% Glycerol formal   40%Tween ® 80   20% NMP q.s.p. 100 ml

Example 8

[0064] A composition comprising: Rafoxanide 12.5% 2-pyrrolidone   40%Tween ® 80   10% Glycerol formal q.s.p. 100 ml

Example 9

[0065] A composition comprising: Rafoxanide 2.5% Acetic acid  10%Tween ® 80  10% NMP  60% Water q.s.p. 100 ml

Example 10

[0066] A composition comprising: Rafoxanide  12% Ivermectin 0.8% Tween ®80  40% NMP q.s.p. 100 ml

[0067] The ingredients are mixed at room temperature and give a clearsolution, which can be used for injections and is miscible with water inall proportions.

[0068] All the above exemplified compositions are stable upon storage atleast for two years at room temperature (+25° C. +/−2° C.)

[0069] The following examples illustrate the efficacy of thecompositions of the present invention and their industrialapplicability.

[0070] Evaluation of the Efficacy of a Composition in Accordance withthe Present Invention in the Treatment of Liver Fluke Infestation inCattle.

[0071] The aim of this study was to evaluate the effect of a treatmentwith a composition in accordance with the present invention (compositionof Example 5) on liver fluke infestation in cattle, and to compare theefficacy of this treatment with the efficacy of a treatment with a 2.5%aqueous rafoxanide suspension.

[0072] Thus, the following experiment was carried out.

[0073] A group of calves infested experimentally or naturally with oneor more liver flukes of the Fasciola hepatica or Fasciola gigantica typeor with gastrointestinal parasites of the Haemonchus placei, Bunostomumphlebotomum or Oesophagostomum radium type, each of immature or adulttype, was used in the experiment.

[0074] Prior to the initiation of the tests, all animals were confirmedto be positively infested by identification of eggs of the parasites inthe faeces.

[0075] The animals were then separated into four groups, and treated asfollows. Three groups were treated by a single subcutaneous injection ofa composition in accordance with Example 5 of the present invention, andrespectively at a dose of rafoxanide of 1, 2 or 3 mg/kg body weight. Thelast group was treated with a single dose of rafoxanide suspension at adose of 7.5 mg/kg of body weight.

[0076] Eight days after the treatment, the animals were killed. In thecase of the animals infested by Fasciola hepatica or Fasciola gigantica,the flukes were collected from the liver, gall bladder and bile duct andcounted. In the case of the other infestations, the entiregastrointestinal content was examined for a counting of the number ofparasites present.

[0077] In each case, the results of the tests were compared to theresults obtained with infested animals which did not receive anytreatment.

[0078] The results are summarised in the following Table I where theeffect of the treatment is expressed as a percentage of reduction of thenumber of parasites. TABLE I % of reduction of the number of parasites2.5% Type of Composition Composition Composition rafoxanide treatment ofEx. 5 of Ex. 5 of Ex. 5 suspension Dose in mg/kg 1 2 3 7.5 body weightParasites adult type F. hepatica 83 98 >99 93 F. gigantica >99 >99 >9995 H. Placei 89 93 >99 97 B. phlebotomum 97 99 >99 91 O. radium 5288 >99 89 Parasites immature type F. hepatica 45 88 89 82 F. gigantica37 74 87 79 H. Placei 35 92 99 92 B. phlebotomum 41 90 95 87 O. radium47 80 88 77

[0079] As is clear from Table I, the treatment with a composition inaccordance with Example 5 of the present invention is more effective inreducing the number of parasites associated with the infestation thanthe treatment using a suspension of rafoxanide in accordance with theprior art, and this even if a lower dose of rafoxanide is given. to theanimal.

[0080] Evaluation of the Efficacy of a Composition in Accordance withthe Present Invention in the Treatment of Liver Fluke Infestation inBuffaloes.

[0081] The aim of this study was to evaluate the effect of a treatmentwith a composition in accordance with the present invention (compositionof Example 5) on liver fluke infestation in buffaloes, and to comparethe efficacy of this treatment with the efficacy of a treatment with a2.5% aqueous rafoxanide suspension.

[0082] Thus, the following experiment was carried out.

[0083] A group of 15 buffaloes infested naturally with Fasciolagigantica was used in the experiment.

[0084] Prior to the initiation of the tests, all animals were confirmedto be positively infested by identification of eggs of the parasites inthe faeces.

[0085] The animals were then separated into three groups each of fiveanimals, and treated as follows. The first group was untreated andserved as control. The second group was treated by a single subcutaneousinjection of a composition in accordance with Example 5 of the presentinvention, at a dose of rafoxanide of 3 mg/kg body weight. The thirdgroup was treated with a single dose of rafoxanide suspension at a doseof 7.5 mg/kg of body weight.

[0086] Ten, eighteen and fifty days after the treatment, a counting ofthe number of parasites present in the faeces was effected. results aresummarised in the following Table II. TABLE II No. of eggs per gram offaeces 10 days 18 days 50 days Before after after after Animal grouptreatment treatment treatment treatment Control 1 56 47 44 49 2 28 30 3031 3 42 42 40 41 4 80 60 58 68 5 52 62 42 57 Composition of Example 5 (3mg/kg body weight) 6 64 — — — 7 80 — — — 8 32 — — — 9 42 — — — 10 70 — —— Rafoxanide suspension (7.5 mg/kg body weight) 11 55  7  6  2 12 78  6 4 — 13 44  1  4  3 14 38  3  7 — 15 69  5  1  2

[0087] As is clear from Table II, the treatment with a composition inaccordance with Example 5 of the present invention is more effective inreducing the number of parasites associated with the infestation thanthe treatment using a suspension of rafoxanide in accordance with theprior art, and this even if a lower dose of rafoxanide is given to theanimal.

[0088] Evaluation of the Efficacy of a Composition in Accordance withthe Present Invention in the Treatment of Liver Fluke Infestation inSheep.

[0089] The aim of this study was to evaluate the effect of a treatmentwith a composition in accordance with the present invention (compositionof Example 5) on liver fluke infestation in sheep, and to compare theefficacy of this treatment with the efficacy of a treatment with a 2.5%aqueous rafoxanide suspension.

[0090] Thus, the following experiment was carried out.

[0091] A group of sheep was infested with Fasciola hepatica byinoculation of 250 viable metacercariae/animal.

[0092] Prior to the initiation of the tests, all animals were confirmedto be positively infested by identification of eggs of the parasites inthe faeces.

[0093] The animals were then separated into four groups, and treated asfollows. Three group were treated by a single subcutaneous injection ofa composition in accordance with

[0094] Example 5 of the present invention, and respectively at a dose ofrafoxanide of 1, 2 or 3 mg/kg body weight. The last group was treatedwith a single dose of rafoxanide suspension at a dose of 7.5 mg/kg ofbody weight.

[0095] Seven days after the treatment, the animals were killed. Theflukes were collected from the liver, gall-bladder and bile duct andcounted.

[0096] In each case, the results of the tests were compared to theresults obtained with infested animals which did not receive anytreatment.

[0097] The results are summarised in the following Table III where theefficacy of the treatment is expressed as a percentage of reduction ofthe number of parasites. TABLE III Average number of flukes and efficacyAverage number of Dose flukes Efficacy in % Control 134.0 +/− 3.4  —Composition of Example 5   1 mg/kg body weight 18.2 +/− 1.3  86.4   2mg/kg body weight 7.1 +/− 0.8 94.7   3 mg/kg body weight  1.2 +/− 0.1199.1 Rafoxanide suspension 7.5 mg/kg body weight  4.7 +/− 0.21 96.5

[0098] As is clear from Table III, the treatment with a composition inaccordance with Example 5 of the present invention is more effective inreducing the number of parasites associated with the infestation thanthe treatment using a suspension of rafoxanide in accordance with theprior art, and this even if a lower dose of rafoxanide is given to theanimal.

[0099] The compositions according to the present invention can thereforebe used as a treatment for animals infested by liver flukes orgastrointestinal parasites.

[0100] Although the present invention has been described with referenceto several examples and embodiments of specific compositions andconcentrations of ingredients, this is not to be considered as alimitation of the invention but merely illustrative thereof.

[0101] Specifically, other compounds like chemical derivatives of theactive compounds cited herein could be used, as soon as the modificationdoes not lead to a substantial loss of the activity of the compound.

1. A micellar composition for the treatment of parasitic diseases inanimals, said composition comprising rafoxanide, a non-ionic surfaceactive agent, and either N-methylpyrrolidone, or 2-pyrrolidone, or acombination of N-methylpyrrolidone with 2-pyrrolidone, or thecombination of dimethylsulfoxide with N-methylpyrrolidone and/or2-pyrrolidone.
 2. A composition according to claim 1 wherein thenon-ionic surface active agent is polyoxyethylene sorbitan monooleate(Tween® 80).
 3. A composition according to claim 1 or 2, which furthercomprises glycerol formal.
 4. A composition according to any one ofclaims 1 to 3 wherein the amount of rafoxanide is between 2.5% and 25%weight/volume.
 5. A composition according to any one of claims 1 to 4wherein the amount of rafoxanide is 12.5% weight/volume.
 6. Acomposition according to any one of claims 1 to 5 wherein the amount ofnon-ionic surface-active agent is between 5 and 50% weight/volume.
 7. Acomposition according to any one of claims 1 to 6, which furthercomprises water and acetic acid.
 8. A composition according to any oneof claims 1 to 7 which further comprises other agents like excipients,preservatives, vitamins, further stabilising agents, carriers,antioxidants, photostabilisers, colorants, further absorption-promotingsubstances, or thickeners.
 9. A composition according to any one ofclaims 1 to 8, which further comprises an anthelmintic antibioticselected from the group consisting of avermectins or their derivatives.10. A composition according to claim 9 wherein the amount of avermectinor derivative thereof in the composition is preferably between 0% and15% weight/volume.
 11. A composition according to claim 9 wherein theanthelmintic antibiotic is ivermectin.
 12. A composition according toclaim 11, which comprises 12% of rafoxanide and 0.8% of ivermectin. 13.A composition according to any one of claims 1 to 12 for use as amedicament.
 14. Use of a composition according to any one of claims 1 to12 for the preparation of a medicament for the therapeutic treatment ofanimal diseases caused by parasitic worms or nematodes.
 15. Use of acomposition according to any one of claims 9 to 12 for the preparationof a medicament for the therapeutic treatment of internal or externaldiseases caused by parasites affecting cattle, buffaloes, sheep andgoats.